Phase 3 Randomized Double-Blind Trial of Ociperlimab and Tislelizumab vs. Pembrolizumab in PD-L1-Selected Advanced Non-Small Cell Lung Cancer
- Trial ID
- 2023-507317-10-00
- Protocol
- BGB-A317-A1217-302
- Sponsor
- Beigene Ltd.
Trial statistics
Objectives
The primary objective of this Phase 3, randomized, double-blind study is to compare **overall survival (OS)** between Arm A, which involves the administration of **ociperlimab** in combination with **tislelizumab**, and Arm B, which involves **pembrolizumab** followed by placebo, in patients with previously untreated, PD-L1-selected, and locally advanced, unresectable, or metastatic non-small cell lung cancer. This objective is clinically relevant as it aims to determine the efficacy of the novel combination therapy in extending the lifespan of patients with this aggressive form of lung cancer.
Secondary objectives include:
- Comparing **progression-free survival (PFS)** between the two treatment arms as assessed by investigators according to the Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1).
- Comparing the **overall response rate (ORR)** and **duration of response (DOR)** between the treatment arms.
- Evaluating **health-related quality of life (HRQoL)** and **time to deterioration (TTD)** between the treatment arms.
- Further investigating the **safety and tolerability** of ociperlimab in combination with tislelizumab.
Participants
The clinical trial involves a total of **525 participants** diagnosed with **locally advanced, unresectable, or metastatic non-small cell lung cancer** (NSCLC). The study population includes both male and female subjects, aged 18 years and older, who have not received prior systemic treatment for metastatic NSCLC. Participants were selected based on specific criteria, including the requirement for histologically or cytologically documented NSCLC that is not eligible for curative surgery or definitive radiotherapy. Additionally, participants must have tumors with PD-L1 expression in at least 50% of tumor cells and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. The trial does not include a vulnerable population. Participants are required to have adequate organ function and must agree to provide archival tissue or a fresh biopsy for central evaluation of PD-L1 levels. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided.
Plans and Procedures
The clinical trial is a **Phase 3**, randomized, double-blind study designed to evaluate the efficacy of **Ociperlimab**, an anti-TIGIT antibody, in combination with **Tislelizumab** compared to **Pembrolizumab** in patients with previously untreated, PD-L1-selected, and locally advanced, unresectable, or metastatic non-small cell lung cancer (NSCLC). The trial aims to compare overall survival (OS) between the two treatment arms. The study is structured to include an initial screening visit, multiple follow-up visits, and an end-of-study visit. The trial is expected to last until August 31, 2025, with participant involvement potentially extending up to 74 weeks, depending on individual response and treatment tolerability.
Participants will undergo a screening visit to confirm eligibility, which includes histological or cytological documentation of NSCLC, assessment of PD-L1 expression, and evaluation of organ function. Eligible participants will be randomized into two arms: Arm A receiving Ociperlimab in combination with Tislelizumab, and Arm B receiving Pembrolizumab followed by placebo. The trial employs a double-blind design to ensure unbiased results. Follow-up visits will occur at regular intervals to monitor treatment efficacy, safety, and adverse events, assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0).
The primary endpoint is overall survival, defined as the time from randomization to death from any cause. Secondary endpoints include progression-free survival (PFS), objective response rate (ORR), duration of response (DOR), health-related quality of life (HRQoL), and time to deterioration (TTD). Participants may be withdrawn from the study early due to disease progression, unacceptable toxicity, or withdrawal of consent. The study's design ensures rigorous monitoring and data collection to achieve its objectives, with all procedures conducted in accordance with ethical guidelines and regulatory requirements.
Treatment
The clinical trial involves the administration of several treatments, including **Ociperlimab**, **Tislelizumab**, and **Pembrolizumab**, as well as a **normal saline solution for infusion**. **Ociperlimab** is provided as a solution for infusion, with a maximum daily dose of 900 mg and a total dose of 1864.8 mg over a treatment period of 74 days. The route of administration is via infusion, and the pharmaceutical form is a solution for infusion. The active substance, ociperlimab, is a protein of other origin, and the product is sponsored by BeiGene under the product code BGB-A1217.
**Tislelizumab** is administered as a concentrate for solution for infusion, with a maximum daily dose of 200 mg and a total dose of 414.4 mg over the same treatment period of 74 days. The administration route is also via infusion. The active substance, tislelizumab, is a protein of other origin, and the product is sponsored by BeiGene with the product code BGB-A317.
**Pembrolizumab**, marketed as KEYTRUDA, is provided as a 25 mg/mL concentrate for solution for infusion. The maximum daily dose is 200 mg, with a total dose of 0.41 kg over 74 days. The administration is conducted via infusion. The active substance, pembrolizumab, is a protein of other origin, and the product is authorized by Merck Sharp & Dohme B.V.
The **normal saline solution for infusion** is used as a non-experimental treatment in the study. It serves as a standard-of-care therapy or placebo, depending on the trial arm. The pharmaceutical form and active substance details are not specified, and it is administered via infusion.
Efficacy
Efficacy in this clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Overall Survival (OS)**, defined as the time from the date of randomization to the date of death due to any cause, evaluated in the Intent-to-Treat (ITT) Analysis Set for both Arm A (ociperlimab in combination with tislelizumab) and Arm B (pembrolizumab followed by placebo). Secondary endpoints include **Progression-Free Survival (PFS)**, assessed by investigators as the time from randomization to the first objectively documented tumor progression per RECIST v1.1 or death, whichever occurs first. Additionally, the **Objective Response Rate (ORR)** and **Duration of Response (DOR)** will be evaluated, with ORR being the proportion of patients with a documented, confirmed complete response or partial response per RECIST v1.1, and DOR being the time from the first determination of an objective response until the first documentation of progression or death.
Health-Related Quality of Life (HRQoL) will be assessed using patient-reported outcomes (PRO) through the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), its lung cancer module Quality of Life Questionnaire Lung Cancer 13 (QLQ-LC13), and the 5 Level EuroQol 5 Dimension (EQ-5D-5L) questionnaire. Time to Deterioration (TTD) will also be measured, defined as the time from randomization to the first occurrence of worsening scores for two consecutive assessments or one assessment followed by death from any cause before the next scheduled data collection. The incidence and severity of adverse events (AEs) will be monitored according to the National Cancer Institute Common Terminology Criteria for Adverse Events Version 5.0 (NCI CTCAE v5.0).
Inclusion and Exclusion Criteria
Inclusion Criteria
- Able to provide written informed consent and can understand and agree to comply with the requirements of the study and the schedule of assessments
- Age ≥ 18 years on the day of signing the informed consent form (or the legal age of consent in the jurisdiction in which the study is taking place).
- Histologically or cytologically documented locally advanced or recurrent NSCLC that is not eligible for curative surgery and/or definitive radiotherapy with or without chemoradiotherapy, or metastatic nonsquamous or squamous NSCLC.
- No prior systemic treatment for metastatic NSCLC.
- Agreement to provide archival tissue (formalin-fixed paraffin-embedded block containing tumor [preferred] or approximately 6 to 15 freshly cut unstained slides) or fresh biopsy (if archival tissue is not available) for central evaluation of PD-L1 levels and retrospective analysis of other biomarkers.
- Tumors with PD-L1 expressed in ≥ 50% tumor cells as determined centrally (or locally in the US and Japan).
- At least 1 measurable lesion as defined per RECIST v1.1. Note: A lesion in an area subjected to prior locoregional therapy, including previous radiotherapy, is not considered measurable unless there has been demonstrated progression in the lesion since the therapy as defined by RECIST v1.1.
- ECOG Performance Status ≤ 1.
- Adequate organ function as indicated by the following laboratory values during screening: a. Patients must not have required blood transfusion or growth factor support ≤ 14 days before sample collection at Screening for the following: Absolute neutrophil count (ANC) ≥ 1.5 x 109/L Platelets ≥ 75 x 109/L Hemoglobin ≥ 90 g/L b. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or estimated glomerular filtration rate ≥ 60 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration (CKD EPI) equation (Appendix 8). Note, for sites in France: Serum creatinine ≤ 1.5 x ULN and estimated glomerular filtration rate or estimated creatinine clearance ≥ 60 mL/min/1.73 m2 by CKD-EPI and Cockcroft and Gault equations, respectively (Appendix 8). c. Serum total bilirubin ≤ 1.5 x ULN (total bilirubin must be < 3 x ULN for patients with Gilberts syndrome). d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN or < 5 x ULN if hepatic metastases present.
- Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 120 days after the last dose of study drug, and must have a negative urine or serum pregnancy test ≤ 7 days before randomization.
- Nonsterile males must be willing to use a highly effective method of birth control for the duration of the study and for ≥ 120 days after the last dose of study drug. • A sterile male is defined as one for whom azoospermia has been previously demonstrated in a semen sample examination as definitive evidence of infertility. • Males with known “low sperm counts” (consistent with “subfertility”) are not to be considered sterile for purposes of this study.
Exclusion Criteria
- Known mutations in a. EGFR gene (Note: Patients with nonsquamous NSCLC whose EGFR mutational status is unknown will be required to have a tissue-based EGFR test either locally or centrally, or endobronchial ultrasound-guided transbronchial needle aspiration [EBUS-TBNA] based EGFR test locally at Prescreening.) Patients found to have EGFR-sensitizing mutations will be excluded. b. ALK fusion oncogene c. BRAF V600E d. ROS1 Note: If no targeted therapy approved by local health authority is available for BRAF V600E or ROS1 mutations, then these patients are eligible. ALK testing is required for patients with nonsquamous NSCLC in Korea, if ALK status is unknown.
- Prior therapy with an anti-PD-1, anti-PD-L1, anti-programmed cell death ligand 2 (PD L2), anti-TIGIT, or any other antibody or drug specifically targeting T-cell costimulation or checkpoint pathways.
- Active leptomeningeal disease or uncontrolled, untreated brain metastasis. Note: Patients with a history of treated and, at the time of screening, stable central nervous system (CNS) metastases are eligible, provided that they meet all the following: Brain imaging at Screening shows no evidence of interim progression, patient is clinically stable for at least 2 weeks and without evidence of new brain metastases. Measurable and/or evaluable disease outside the CNS. No ongoing requirement for corticosteroids as therapy for CNS disease; off steroids 3 days before randomization; anticonvulsants at a stable dose are allowed. No stereotactic radiation or whole-brain radiation within 14 days before randomization.
- Active autoimmune diseases or history of autoimmune diseases that may relapse. Note: Patients with the following diseases are not excluded and may proceed to further screening: a. Controlled Type I diabetes. b. Hypothyroidism (provided it is managed with hormone replacement therapy only). c. Controlled celiac disease. d. Skin diseases not requiring systemic treatment (eg, vitiligo, psoriasis, alopecia). e. Any other disease that is not expected to recur in the absence of external triggering factors.
- Any active malignancy ≤ 5 years before randomization except for the specific cancer under investigation in this study, those with a negligible risk of metastasis or death, and any locally recurring cancer that has been treated curatively (eg, resected basal or squamous cell skin cancer, superficial bladder cancer, localized prostate cancer, or carcinoma in situ of the cervix or breast).
- Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone [in Japan, prednisolone] or equivalent) or other immunosuppressive medication ≤ 14 days before randomization. Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded: a. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone [in Japan, prednisolone] or equivalent). b. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption. c. Short course (≤ 7 days) of corticosteroid prescribed prophylactically (eg, for contrast dye allergy) or for the treatment of a non-autoimmune condition (eg, delayed-type hypersensitivity reaction caused by contact allergen.
- Uncontrolled diabetes or > Grade 1 laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management or ≥ Grade 3 hypoalbuminemia ≤ 14 days before randomization.
- Uncontrollable pleural effusion, pericardial effusion, or ascites requiring frequent drainage (recurrence within 2 weeks of intervention). Patients with symptomatic pleural effusion are excluded unless the patient undergoes a therapeutic thoracentesis or has had pleurodesis (more than 2 weeks prior) and has subsequently stable effusions.
- History of interstitial lung disease, noninfectious pneumonitis or uncontrolled lung diseases including pulmonary fibrosis, acute lung diseases, etc. All patients must undergo an assessment of pulmonary function at Screening
- Infection (including tuberculosis infection, etc) requiring systemic antibacterial, antifungal, or antiviral therapy within 14 days before randomization, or patients who tested positive for COVID-19 antigen by a licensed test during screening. Note: Antiviral therapy is permitted for patients with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
- Untreated chronic hepatitis B or chronic HBV carriers with HBV DNA > 500 IU/mL (or > 2500 copies/mL) at Screening. Note: Inactive hepatitis B surface antigen (HBsAg) carriers, (in Japan, defined as patients who are HBsAg-positive but asymptomatic), treated and stable hepatitis B (HBV DNA < 500 IU/mL or < 2500 copies/mL) can be enrolled. Patients with detectable hepatitis B surface antigen (HBsAg) or detectable HBV DNA should be managed per treatment guidelines. Patients receiving antivirals at Screening should have been treated for > 2 weeks before randomization.
- Patients with active hepatitis C. Note: Patients with a negative HCV antibody test at Screening or positive HCV antibody test followed by a negative HCV RNA test at Screening are eligible. The HCV RNA test will be performed only for patients testing positive for HCV antibody. Patients receiving antivirals at Screening should have been treated for > 2 weeks before randomization.
- Known history of HIV infection, or if HIV status is unknown, positive HIV test at Screening.
- Any major surgical procedure ≤ 28 days before randomization. Patients must have recovered adequately from the toxicity and/or complications from the intervention before randomization.
- Prior allogeneic stem cell transplantation or organ transplantation.
- Any of the following cardiovascular risk factors: a. Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, ≤ 28 days before randomization. b. Symptomatic pulmonary embolism diagnosed ≤ 28 days before randomization. c. Any history of acute myocardial infarction ≤ 6 months before randomization. d. Any history of heart failure meeting New York Heart Association (NYHA) Classification III or IV ≤ 6 months before randomization. e. Any event of ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before randomization. f. Any history of cerebrovascular accident ≤ 6 months before randomization. g. Uncontrolled hypertension that cannot be managed by standard antihypertension medications ≤ 28 days before randomization. For France only, specify: Systolic pressure ≥ 140 mmHg or diastolic pressure ≥ 90 mmHg on repeated measurements. h. Any episode of syncope or seizure ≤ 28 days before randomization.
- A history of severe hypersensitivity reactions to other monoclonal antibodies or a history of hypersensitivity to the ingredients of tislelizumab or ociperlimab.
- Was administered a live vaccine ≤ 28 days before randomization. Note: Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed.
- Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that will be unfavorable for the administration of study drug or that will affect the explanation of drug toxicity or AEs, or result in insufficient or impaired compliance with study conduct.
- Women who are pregnant or are breastfeeding.
- Concurrent participation in another therapeutic clinical study. Note: Concurrent participation in observational or noninterventional studies is allowed. In addition, patients who have completed active treatment in a clinical study and are in the follow up period can be enrolled in this study.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Not Recruiting | 03 Aug 2021 | 40 |
 Germany | Not Recruiting | 03 Aug 2021 | 10 |
 Italy | Not Recruiting | 03 Aug 2021 | 4 |
 The Netherlands | Not Recruiting | 03 Aug 2021 | — |
 Poland | Not Recruiting | 03 Aug 2021 | 8 |
 Spain | Not Recruiting | 03 Aug 2021 | 64 |
| Netherlands | — | — | 9 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
normal saline solution for infusion | Placebo | N/A | — | — | — | N/A |
Ociperlimab | Test | SOLUTION FOR INFUSION | INFUSION | 900 | 74 | PRD10987941 |
KEYTRUDA 25 mg/mL concentrate for solution for infusion | Comparator | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 200 | 74 | PRD4323105 |
Tislelizumab | Test | CONCENTRATE FOR SOLUTION FOR INFUSION | INFUSION | 200 | 74 | PRD10156087 |
Ociperlimab | Test | SOLUTION FOR INFUSION | INFUSION | 900 | 74 | PRD9450026 |